Sickle Cell Abnormalities and Acute Porphyria

Marjorie A. Lewis

Salvatore R. Goodwin

PART I SICKLE CELL DISEASE

CASE SUMMARY

A 38-kg, 16-year-old, African American man with a history of sickle cell disease (SCD) is scheduled for a cholecystectomy. He has had multiple hospitalizations for painful crisis, acute chest syndrome (ACS), and priapism, and has often required transfusion therapy. He suffered a cerebrovascular accident (CVA) 1 year ago that has left him with a right-sided hemiparesis and mild cognitive dysfunction. The patient has been on a transfusion protocol since the CVA. His hemoglobin (Hb) is 8.2 g per dL, and his liver enzymes are mildly elevated.

The patient was admitted the day before surgery and received 10 mL per kg of packed red blood cells that raised his Hb to 10.1 g per dL and lowered his HbS to 31%. The patient received intravenous hydration before and during an uneventful general anesthetic for a laparoscopic cholecystectomy. In the postanesthesia care unit, he developed shivering and pain, and subsequently became combative and agitated. His pulse oximeter oxygen saturation (SpaO₂) dropped to 85%, and he developed a hacking, dry cough. A chest radiograph demonstrated a new left lower lobar infiltrate.

Treatment includes supplemental oxygen, intravenous fluids, a forced air warming blanket, and morphine. He is admitted to the intensive care unit for treatment of ACS. He then developed respiratory failure, which required 1 week of mechanical ventilation, and is eventually discharged after a 4-week hospital course.

INTRODUCTION

Anesthesiologists are frequently called upon to care for patients with hemoglobinopathies. As in this case, the complications of the disease often occur in the postoperative period. Adequate preoperative preparation, intraoperative and postoperative management may prevent many of the complications associated with this disease.

What Is the Genetic Cause of Sickle Cell Disease?

Hb consists of two α chains and two non-α chains. In the case of normal adult Hb, these non-α chains are β chains. The α chain production is coded by two alleles located in the chromosome 11, whereas the β chain production is controlled by four alleles paired on chromosome 16. Abnormal Hb states can result from underproduction of a globin chain or production of an abnormal amino acid sequence within a chain.

Underproduction of a given chain results in the group of disorders known as thalassemia. α-Thalassemia is the underproduction of the α chain. There are four types of α-thalassemia, ranging in severity from mild to severe, depending on how many of the four α-globulin chains are underproduced. β-Thalassemia is commonly seen in people from the Mediterranean Sea region. It results from an underproduction of β chains. Heterozygotes have a mild anemia known as thalassemia minor. Homozygotes are known as thalassemia major, or Cooley’s anemia, and are usually transfusion-dependent. Patients may be genetically coded to have both a sickling disorder and one of the thalassemias.

SCD is the most common of all hereditary disorders, affecting up to 0.2% of the adult African American population with SCD, 8% with sickle cell trait,¹ and approximately 50,000 children in the United States with SCD.²,³ A single amino acid substitution at position 6 on the β chain is responsible for the condition. SCD is inherited as an autosomal recessive disorder following a predictable Mendelian pattern. Therefore, heterozygote (HbAS) parents will have a 25% chance of producing either a normal (HbAA) or SCD (HbSS) and a 50% chance of producing another heterozygote (HbSA, trait) child.

Normal adult red blood cells contain three types of Hb, HbA (α₂,β₂) and small quantities of HbA₂ (α₂,δ₂) and
HbF (α₂γ₂). Patients with SCD have >50% HbS, with the remainder being HbF or HbA₂ (see Table 37.1). They contain no HbA unless they have a double heterozygous condition such as both SCD and β-thalassemia. However, they will always have more than 50% HbS. Individuals with a combination of normal HbA and <50% HbS have sickle cell trait. Infants may have >70% HbF, which persists for up to 4 months of age when the fetal red cells are replaced by hematopoiesis of adult red cells as β chain production replaces γ chain production. When fetal Hb is present and persists into adulthood, it can provide protection against sickling. HbC and thalassemia β⁺ also provide some protection against sickling, and these patients usually have a milder clinical course.

TABLE 37.1 Genotype and Hemoglobin Electrophoresis Patterns in Various Hemoglobinopathy Syndromes

Hemoglobinopathy Syndrome	Genotype	Neonatal Electrophoresis	HbA %	HbS %	HbF %	HbC %
Sickle cell trait	HbSA	FAS	55-60	<50	1-2	0
Sickle β⁺ thalassemia	HbSβ⁺	FAS or FS	15-30	55-75	2-20	0
Hemoglobin SC disease	HbSC	FSC	0	45-55	2-8	45-55
Sickle β⁰ thalassemia	HbSβ⁰	FS	0	50-80	2-30	0
Sickle cell disease	HbSS	FS	0	>80	2-20	0
HbA, hemoglobin A; HbS, sickle hemoglobin; HbF, fetal hemoglobin; HbC, hemoglobin C; HbSβ+, hemoglobin sickle β+ thalassemia; HbSβ⁰, hemoglobin sickle β⁰ thalassemia; β⁰, thalassemias with absent production of β globin; β+, thalassemias with reduced but not absent production of β globin.

What Background Knowledge Is Relevant for Sickle Cell Disease?

In SCD, there is a glutamic acid to valine substitution at position 6 on the 146 amino acid β chain. This substitution creates a structural abnormality of the Hb molecule, rendering it unstable, as well as less soluble when deoxygenated. The former causes accelerated breakdown and hemolytic anemia, whereas the latter permits Hb tetramers to form polymers.⁴ These Hb polymers form long helical bands, causing distorted red cells.⁵ As the cells sickle and reform, the intricate balance of iron metabolism and cellular hydration is disturbed, which alters the red cell membrane, thereby making them sticky. Historically, it was felt that this red cell abnormality was solely responsible for SCD-related problems. However, the interactions between red cells, platelets, leukocytes, thrombin, and endothelial cells, along with disturbances of nitric oxide (NO) biology, are now known to be at least equally important. Recent evidence shows that there is decreased production and increased scavenging of NO in patients with SCD. Through different mediators, this leads to a complex pathophysiology, including endothelial dysfunction, enhanced platelet aggregation and coagulation, increased leukocyte endothelial adhesion, susceptibility to oxidantmediated injuries, and both acute and chronic pulmonary hypertension. In fact, the administration of inhaled NO has been shown to be beneficial in some patients suffering a vaso-occlusive crisis, including stroke and ACS.

With time, these complex interactions between the deformed and sticky red cells and the endothelium results in widespread chronic endothelial inflammation, injury, and organ dysfunction.

The HbS red cell is unstable and insoluble, resulting in early red cell destruction, sickling, and endothelial damage. Red blood cells with HbSS begin sickling when the oxygen saturation falls below 85% (PaO₂ of approximately 40 to 50 mmHg). Acidosis, hypoxia, intracellular dehydration, and vascular stasis increase the sickling process (see Table 37.2). Decreased cardiac output and hypovolemia lead to increased transit time through the hypoxic environment of the capillary bed, also increasing the sickling process. The consequence of sickling is endothelial adhesion and occlusion of the microvasculature. Erythrocytes, leukocytes, platelets, vascular endothelium, NO, and the coagulation cascade are involved in the vascular injury that results from the sickled red blood cell. In fact, SCD should be considered as much a vascular endothelial disease as a red blood cell disease.

TABLE 37.2 Physiologic Conditions which Tend to Increase the Chance of Sickling in Patients with Sickle Cell Disease

Deoxygenation of Hemoglobin
PULMONARY CAUSES
	Pneumonia
	Atelectasis
	Hypoventilation
	Bronchospasm
	Chronic obstructive pulmonary disease
	High altitude or hypoxic environment
OXYGEN DELIVERY
	Decreased cardiac output
	Decreased contractility
	Hypovolemia
	Sepsis
	Anesthesia
	Severe anemia
INCREASED EXTRACTION
	Acidosis
	Sepsis
	Vigorous exercise
	Malignant hyperthermia
INCREASED TRANSIT TIME
	Dehydration
	Excessive transfusion
	Hypothermia
	Orthopedic tourniquet

TABLE 37.3 Age-Specific Clinical Complications Often Present in Patients with Sickle Cell Disease

Age	Condition	Clinical Presentation
Infant	Dactylitis	Painful vaso-occlusion, hand-foot syndrome
	Splenic sequestration	Anemia, hypovolemia, death
Child	Aplastic crisis	Bone marrow hypoplasia, severe anemia
	Splenic infarction	Prone to infection with encapsulated organisms
	Infection	Sepsis, osteomyelitis, Staphylococcus or Salmonella
	Vaso-occlusive crisis	Pain, usually of the extremities, may be abdominal
	Reactive airway disease	May lead to acute chest syndrome
	Enuresis	Inability to concentrate urine
Adolescent to adult	Acute chest syndrome	Chest pain, fever, cough, new infiltrate on CXR
	Stroke	Microinfarcts or hemorrhagic
	Priapism	May lead to impotence
	Leg ulcers	—
	Cholelithiasis	Pigment gallstones due to hemolysis
	Chronic renal insufficiency	—
	Hematuria	—
	Orbital infarction	—

What Are the Clinical Manifestations of Sickle Cell Disease?

Sickle cell problems begin in infancy and culminate in multiorgan damage in adulthood after years of endothelial damage, microinfarcts and ischemic damage to end organs (see Table 37.3). Because of immunologic deficits and splenic dysfunction, these patients are at very high risk for overwhelming sepsis. One of the main reasons for widespread postnatal screening for this disease is so children can be placed on penicillin until the age of 6 to assure appropriate immunoprophylaxis. The clinical manifestations of SCD can be grouped into acute and chronic. Typically, the acute problems have been grouped as various crises: Splenic sequestration, hyperhemolytic, aplastic, and vaso-occlusive. The vaso-occlusive crisis can be further broken down into: Painful, priapism, ACS, and stroke. It is these vaso-occlusive events that are of the most concern during the perioperative period.

ACS and stroke are the most concerning perioperative complications. ACS may result from pneumonia, fat emboli, pulmonary vaso-occlusion, and sequestration. It occurs in 10% to 20% of postoperative patients,⁶,⁷,⁸ and may rapidly progress to respiratory failure. The mortality rate from ACS is 2% to 12%. This, more than anything else, accounts for the very high perioperative mortality rate of 1% in these patients. Treatment for ACS includes supplemental oxygen, exchange transfusion, hydration, aggressive respiratory support, and antibiotics (see Table 37.4). Inhaled NO may also have a unique role in treating ACS.⁸

Cerebral vascular accidents occur in approximately 5% of subjects with SCD.⁹ Most CVAs in children are due to ischemic infarcts, whereas adults may also be hemorrhagic. It has recently been recognized that as many as 15% to 25% of asymptomatic children have radiographic evidence of silent cerebral infarcts. In many centers, patients with SCD are screened with transcranial Doppler, and those with elevated flow velocities in the middle cerebral and terminal internal carotid arteries are placed on hypertransfusion regimens. Individuals with a previously documented CVA are placed on transfusion regimens, usually for a period of 10 years. It is only recently that we are noting that patients coming off these regimens are experiencing recurrence.

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